Are common
Before starting therapy with tenofovir, an antibody test for HIV should be offered to all patients infected with hepatitis B virus.
HIV-1
Despite the fact that stable antiretroviral therapy, leading to sustained suppression of the virus, significantly reduces the risk of transmission of the virus during sexual intercourse, however, the risk can not be ruled out completely. Precautions to prevent transmission should be taken in accordance with national guidelines.
Chronic hepatitis B
Patients should be warned that the ability of tenofovir to prevent the risk of transmission of HBV to others through sexual contact or through the blood has not been proven.Appropriate precautions should be taken.
Simultaneous use with other drugs
- Tenofovir BM should not be used with other medicines containing tenofovir.
- Tenofovir BM should not be used concomitantly with adefovir.
- It is not recommended simultaneous use of tenofovir and didanosine. The simultaneous use of tenofovir and didanosine leads to a 40-60% increase in the systemic exposure of didanosine, which may increase the risk of ddI related to didanosine (see "Interactions with Other Drugs" section). Rarely reported on pancreatitis and lactic acidosis, sometimes with a fatal outcome. Simultaneous use of tenofovir and didanosine at a dose of 400 mg per day was associated with a significant decrease in the number of cells Cd4, possibly due to intercellular interaction, which increases the phosphorylated (i.e., active) didanosine. The use of didanosine at a reduced dosage of 250 mg, together with tenofovir therapy, was associated with reports of a high incidence of virologic failure in several combinations studied for the treatment of HIV-1 infection.
Triple therapy with nucleosides / nucleotides
There have been reports of a high incidence of virological failure and the emergence of resistance at an early stage in patients with HIV infection, if tenofovir was combined with lamivudine and abacavir, as well as with lamivudine and didanosine according to the regimen of administration once a day.
Effect on kidney function and bone tissue in adults
Effect on kidney function
Tenofovir is mainly excreted by the kidneys. There have been reports of renal failure, impaired renal function, elevated creatinine, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) with tenofovir in clinical practice (see "Side-Effects" section).
Control of kidney function
It is recommended that the CC be determined in all patients before starting treatment with tenofovir and monitoring kidney function (QA and serum phosphate) after 2-4 weeks of treatment, at 3 months of treatment, and every 3-6 months after patients without risk factors for renal dysfunction. For patients with an increased risk of renal failure, the need for more frequent monitoring of kidney function should be considered.
Management of patients with impaired renal function
If serum phosphate levels <1.5 mg / dL (0.48 mmol / L) or QC are reduced to <50 ml / min in the patient receiving tenofovir, it is necessary to reassess the function of the kidneys within 1 week, including determining the level of glucose in the blood, potassium in the blood and the concentration of glucose in the urine. The need to discontinue tenofovir treatment in patients with a reduction in CK to <50 ml / min or a decrease in serum phosphate to <1.0 mg / dL (0.32 mmol / L) should also be considered. The withdrawal of tenofovir treatment should also be considered in the event of a progressive decline in renal function if no other cause has been identified.
Joint use with other drugs and risk of nephrotoxicity
It is necessary to avoid the use of tenofovir with simultaneous or recent use of nephrotoxic drugs (for example, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir and interleukin-2). If simultaneous use of tenofovir and nephrotoxic drugs is not possible, weekly monitoring of kidney function is necessary.
Cases of acute renal failure were reported after initiating therapy with a high dose or several non-steroidal anti-inflammatory drugs (NSAIDs) in patients who received tenofovir and having risk factors for renal dysfunction. Renal function should be monitored appropriately by the simultaneous use of tenofovir and NSAIDs.
A high risk of kidney damage has been reported in patients receiving tenofovir in combination with a protease inhibitor with enhanced ritonavir or a cobicystate. These patients require careful monitoring of kidney function (see section "Interaction with other drugs"). In patients with risk factors for renal dysfunction, joint use of tenofovir with an enhanced protease inhibitor should be carefully analyzed.
Clinical evaluation of the use of tenofovir was not performed in patients taking medications that are also excreted by the kidneys, through transport proteins of human organic anion transporters (hOAT) 1 and 3 or MRP4 (eg, cidofovir, a known nephrotoxic drug).These kidney transport proteins may be responsible for tubular secretion and, in part, the excretion of tenofovir and cidofovir through the kidneys. Therefore, the pharmacokinetics of drugs that are also excreted by the kidneys, including transport proteins hOAT 1 and 3 or MRP 4, can be changed in case of simultaneous application. In the absence of emergency, the simultaneous use of medicines, which are withdrawn by the same routes through the kidneys, is not recommended. If this can not be avoided, the kidney function should be monitored weekly (see "Interaction with other medicines").
Impaired renal function
The safety of tenofovir against the kidneys has been studied to a very limited extent in patients with impaired renal function (CC <80 mL / min).
Adult patients with CC <50 ml / min, including patients who need hemodialysis
Data on the safety and efficacy of tenofovir for patients with impaired renal function are limited. For this reason tenofovir It is necessary to apply only if the potential benefit of treatment exceeds potential risks.The use of tenofovir in patients with severe renal dysfunction (CK <30 ml / min) and patients who need hemodialysis is contraindicated.
Effects on bone tissue
In a controlled 144-week clinical trial comparing tenofovir with stavudine in combination with lamivudine and efavirenz in HIV-infected adult patients who had not previously received antiretroviral treatment, small decreases in the BMD in the femur and spine were observed in both groups. Decrease in the BMD of the spine and changes from baseline biomarkers of bone tissue metabolism were significantly more pronounced in the tenofovir group at week 144. The decrease in the BMD of the femur was significantly more pronounced in this group up to 96 weeks. However, after 144 weeks of increased risk of fractures or signs of clinically significant pathologies of bone tissue was not observed.
Pathological changes in bone tissue (occasionally leading to fractures) can be caused by damage to the proximal tubule of the kidney (see section "Side effect").
If you suspect or detect pathological changes in bone tissue, consult a specialist.
Effect on kidney function and bone tissue in children from 12 to 18 years of age
The long-term consequences of the effect on bone tissue and the toxic effects on the kidneys in children have not been fully established. In addition, the reversibility of toxic effects on the kidney is not fully established. Therefore, it is recommended that a multilateral approach be used to adequately determine the benefit / risk ratio in each case, decide on appropriate follow-up during treatment (including deciding whether to discontinue therapy), and consider the appropriateness of using additional drugs.
Control of kidney function
Before starting treatment, it is necessary to evaluate the kidney function (QC and serum phosphate levels), and also to observe during treatment, as well as for adults (see above).
Management of patients with impaired renal function
If any patient of child age receiving tenofovir, serum phosphate levels <3,0 mg / dl (0.96 mmol / L), renal function should be reassessed within 1 week, including blood glucose, potassium in blood, and glucose in urine. If there is a suspicion of renal impairment or detection, it is necessary to consult with the nephrologist to consider the need to cancel the treatment with tenofovir.The withdrawal of tenofovir treatment should also be considered in the case of progressive decline in renal function, when no other cause has been determined.
Joint use and risk of nephrotoxicity
Follow the same recommendations that apply to adults (see above).
Impaired renal function
It is not recommended to apply tenofovir in children with impaired renal function (see section "Method of administration and dose"). Do not start therapy with tenofovir in children with impaired renal function, and it is also necessary to cancel treatment in those children who have developed renal dysfunction during tenofovir therapy.
Effects on bone tissue
Tenofovir VM may cause a decrease in BMD. The effect of changes in BMD associated with tenofovir on bone tissue in the long term and the risk of fractures in the future is currently unknown (see the section "Pharmacodynamics").
If a bone pathology is detected or suspected, children should consult an endocrinologist and / or nephrologist.
Diseases of the liver
Data on safety and efficacy for patients after liver transplantation are very few.
Data on the safety and efficacy of tenofovir for patients with chronic hepatitis B, with uncompensated liver cirrhosis and grade> 9 on Child-Pugh classification are limited. Such patients may have a higher risk of serious adverse reactions from the liver and kidneys. Therefore, the parameters of the hepatobiliary system and kidneys in this category of patients should be closely monitored.
Exacerbation of hepatitis
Exacerbation during treatment
Spontaneous exacerbations of chronic hepatitis B are relatively frequent and are characterized by a temporary increase in the level of alanine aminotransferase (ALT) in serum. After the onset of antiviral treatment in some patients, the level of ALT in the blood serum may increase (see section "Side effect"). In patients with compensated liver disease, elevated serum ALT levels are usually not accompanied by an increase in serum bilirubin concentration or decompensated liver function. Patients with cirrhosis of the liver may have an increased risk of decompensating liver function after exacerbation of hepatitis, so they need careful monitoring during treatment.
Aggravation after discontinuation of treatment
Also reported was exacerbation of hepatitis in patients who discontinued treatment of hepatitis B. Aggravations after withdrawal of therapy are usually associated with an increase in the concentration of DNA of hepatitis B virus, and most of them are resolved without additional interventions. However, severe exacerbations, including lethal cases, have been reported. Within 6 months after stopping the treatment of hepatitis B, it is necessary to regularly monitor the functional state of the liver according to clinical and laboratory parameters. If necessary, it may be advisable to resume treatment for hepatitis B. For patients with progressive liver disease or with cirrhosis, discontinuation of treatment is not recommended, since exacerbation of hepatitis after the abolition of therapy can lead to decompensation of liver function.
In patients with uncompensated cirrhosis, exacerbation of hepatitis occurs particularly seriously, sometimes with a fatal outcome.
Concomitant infection with hepatitis C viruses or D
Data on the efficacy of tenofovir in patients with concomitant hepatitis C virus infection or D are absent.
Concomitant HIV-1 infection and hepatitis B virus
Due to the risk of developing HIV resistance in patients with concomitant HIV / HBV infection tenofovir should only be used as part of the appropriate antiretroviral combination regimen. Patients who have previously been diagnosed with liver disease, including chronic active hepatitis, have an increased incidence of liver function abnormalities during combined antiretroviral therapy and should be monitored in accordance with standard practice. With worsening of the course of liver disease in such patients, consideration should be given to the need for interruption in treatment or withdrawal of treatment. However, it should be noted that elevated ALT levels may be part of a positive antiviral response to HBV for tenofovir therapy, see above "Exacerbation of hepatitis."
Lactic acidosis
With the use of nucleoside analogues, lactic acidosis, usually accompanied by fatty liver dystrophy, has been reported. Preclinical and clinical data indicate that the risk of lactic acidosis, as an effect of drugs from the class of nucleoside analogs, for tenofovir is low. But, since tenofovir structurally similar to nucleoside analogs, this risk can not be ruled out. Early signs (symptomatic hyperlactatemia) include mild symptoms of the digestive system (nausea, vomiting and abdominal pain), nonspecific malaise, loss of appetite, weight loss, respiratory system symptoms (frequent and / or deep breathing) or neurological symptoms symptoms (including motor weakness). Lactic acidosis has a high lethality and may be accompanied by pancreatitis, hepatic or renal insufficiency. Usually, lactic acidosis is observed after several months of treatment.
Treatment with analogues of nucleosides should be discontinued in the presence of symptomatic hyperlactatemia and metabolic / lactic acidosis, progressive hepatomegaly or a rapid increase in the level of aminotransferases. Caution should be exercised when assigning nucleoside analogs to any patient (especially obese women) with hepatomegaly, hepatitis, or other known risk factors for liver disease and fatty liver disease (including certain drugs and alcohol).Interferon-alpha and ribavirin treatment of patients with concomitant hepatitis C virus infection may present a particular risk.
Patients with an increased risk should be closely monitored.
Lipodystrophy
In patients with HIV infection, combined antiretroviral therapy was associated with the redistribution of adipose tissue in the body (lipodystrophy). The remote consequences of these phenomena are unknown to date. Data on the mechanism of development are incomplete. There is a hypothesis about the relationship between the development of visceral lipomatosis and the intake of protease inhibitors and the development of lipoatrophy with the use of nucleoside reverse transcriptase inhibitors. The increased risk of lipodystrophy was due to individual factors, such as the elderly age of patients, and factors associated with the drug, such as the long duration of antiretroviral therapy and the resulting metabolic disorders. Clinical examination should include an assessment of the physical signs of redistribution of adipose tissue in the body. You should pay attention to the indices of lipids of blood serum fasting and the level of glucose in the blood.Dyslipidemia should be adjusted in accordance with clinical recommendations.
Tenofovir is structurally related to nucleoside analogs, so the risk of developing lipodystrophy can not be ruled out. However, 144-week data obtained from HIV-infected patients who have not previously been treated with antiretroviral agents, indicate that the risk of lipodystrophy in the case of tenofovir was smaller than when taking stavudine, when they were used in combination with lamivudine and efavirenz.
Mitochondrial disorders
In vitro and in vivo it was shown that nucleoside and nucleotide analogues lead to damage to mitochondria of different degrees. There have been reports of the development of mitochondrial disorders in HIV-negative newborns exposed intrauterine and / or postnatal effects of nucleoside analogues. The main undesirable phenomena reported were hematologic disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipazemia). These phenomena are often short-lived. There were reports of some neurological disorders that began later (hypertension, seizures, abnormal behavior).To date, it is not known whether neurological disorders are temporary or permanent. All children exposed to prenatal exposure to nucleoside or nucleotide analogues, even HIV-negative newborns, should be under close clinical and laboratory supervision and have a thorough examination for possible presence of mitochondrial changes in case of manifestation of the corresponding signs or symptoms. The available data do not influence the current national recommendations, according to which HIV-positive pregnant women need antiretroviral therapy to prevent vertical transmission of HIV.
Immunodeficiency Syndrome
At the onset of antiretroviral therapy in HIV-infected patients with severe immunodeficiency, an inflammatory response to pathogens of asymptomatic or residual opportunistic infections may occur and lead to severe clinical conditions or increased severity of symptoms. Typically, such reactions are observed during the first weeks after the start of treatment.Examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infections and pneumocystis (Pneumocystis jirovecii) pneumonia. You should monitor any symptoms of inflammation and, if necessary, prescribe treatment in a timely manner. Also reported were autoimmune diseases (such as Graves' disease) that accompanied reactivation of immunity; However, the time of onset of such events varies greatly, and these cases may have occurred several months after the start of treatment.
Osteonecrosis
Although the etiology of osteonecrosis is considered multifactorial (including the use of glucocorticosteroids, alcohol use, the presence of severe immunosuppression, a higher body mass index), cases of osteonecrosis have been recorded especially frequently in patients with progressive HIV infection and / or with prolonged use of combined antiretroviral therapy. Patients should be advised to seek medical advice if they develop aches or joint pain, joint stiffness, or difficulty walking.
Elderly patients
Tenofovir has not been studied in patients older than 65 years.Older patients are more likely to have impaired renal function, so caution should be exercised in treating elderly patients with tenofovir.